While the dynamics of the intracellular surface in agonist-stimulated GPCRs is well studied, the impact of GPCR dynamics on G-protein selectivity remains unclear. Here, we combine molecular dynamics simulations with live-cell FRET and secondary messenger measurements, for 21 GPCR−G-protein combinations, to advance a dynamic model of the GPCR−G-protein interface. Our data show C terminus peptides of Gα s , Gα i , and Gα q proteins assume a small ensemble of unique orientations when coupled to their cognate GPCRs, similar to the variations observed in 3D structures of GPCR−G-protein complexes. The noncognate G proteins interface with latent intracellular GPCR cavities but dissociate due to weak and unstable interactions. Three predicted mutations in β 2 -adrenergic receptor stabilize binding of noncognate Gα q protein in its latent cavity, allowing promiscuous signaling through both Gα s and Gα q in a dose-dependent manner. This demonstrates that latent GPCR cavities can be evolved, by design or nature, to tune G-protein selectivity, giving insights to pluridimensional GPCR signaling.G-protein−coupled receptor | GPCR | functional selectivity | structural plasticity | dynamics Author contributions: M.S.

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While allosteric modulation of GPCR signaling has gained prominence to address the need for receptor specificity, efforts have mainly focused on allosteric sites adjacent to the orthosteric ligand‐binding pocket and lipophilic molecules that target transmembrane helices. In this study, we examined the allosteric influence of native peptides derived from the C‐terminus of the Gα subunit (G‐peptides) on signaling from two Gi‐coupled receptors, adenosine A1 receptor (A 1 R) and cannabinoid receptor 1 (CB 1 ). We expressed A 1 R and CB 1 fusions with G‐peptides derived from Gαs, Gαi, and Gαq in HEK 293 cells using systematic protein affinity strength modulation (SPASM) and monitored the impact on downstream signaling in the cell compared to a construct lacking G‐peptides. We used agonists N 6 ‐Cyclopentyladenosine (CPA) and 5’‐ N ‐Ethylcarboxamidoadenosine (NECA) for A 1 R and 2‐Arachidonoylglycerol (2‐AG) and WIN 55,212‐2 mesylate (WN) for CB 1 . G‐peptides derived from Gαi and Gαq enhance agonist‐dependent cAMP inhibition, demonstrating their effect as positive allosteric modulators of Gi‐coupled signaling. In contrast, both G‐peptides suppress agonist‐dependent IP 1 levels suggesting that they differentially function as negative allosteric modulators of Gq‐coupled signaling. Taken together with our previous studies on Gs‐coupled receptors, this study provides an extended model for the allosteric effects of G‐peptides on GPCR signaling, and highlights their potential as probe molecules to enhance receptor specificity.

Background Myotonic dystrophies (DM) are multisystemic diseases characterised by muscle weakness and myotonia. Despite a growing appreciation for the cardiovascular manifestations in myotonic dystrophy type 1 (DM1), cardiac involvement in myotonic dystrophy Type 2 (DM2) has been less well characterised. In patients with myotonic dystrophy Type 2, cardiomyopathy has rarely been described. Case Summary This case report describes a rare case of myotonic dystrophy Type 2 (DM2) associated cardiomyopathy. 56-year-old male with myotonic dystrophy Type 2 who presented with palpitations and fatigue. Cardiac magnetic resonance imaging (CMR) confirmed a severely enlarged left ventricular cavity with a left ventricular ejection fraction of 28% consistent with severely reduced global systolic function. The lateral wall epicardium exhibited late gadolinium enhancement in a pattern seen in myotonic dystrophy-related cardiomyopathy. Discussion This case highlights the potential for significant cardiovascular involvement in myotonic dystrophy Type 2 (DM2), as well as the importance of screening, including cardiac magnetic resonance imaging (CMR), and therapy in the myotonic dystrophy patient population.

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